Regulation of synapse composition by protein acetylation: the role of acetylated cortactin

Abstract

SummaryProtein acetylation affects synaptic plasticity and memory, but its effects on synapse composition have not been addressed. We found that protein acetylation promotes the dendritic clustering of the excitatory postsynaptic scaffold protein PSD95 in hippocampal neurons, without affecting the total levels of this protein. Cortactin, an F-actin-binding protein enriched in dendritic spines, is a substrate for acetylation and has a role in spine morphogenesis. Recent studies showed that cortactin acetylation changes its ability to bind F-actin and regulates cellular motility, but the function of cortactin acetylation in neuronal cells is so far unknown. We tested whether acetylation of cortactin influences its morphogenic function by overexpressing wild-type cortactin, or the mimetic mutants for acetylated or deacetylated cortactin, in hippocampal neurons, and found that cortactin acetylation has an impact on PSD95 clustering, independent from its function as actin dynamics regulator. Moreover, acetylated cortactin can rescue the reduction in PSD95 clustering mediated by knockdown of cortactin. We also found that acetylation of cortactin is correlated with decreased cortactin interaction with p140Cap and Shank1, and with lower cortactin phosphorylation at tyrosine 421. The neurotrophin BDNF promoted the acetylation of cortactin in hippocampal neurons, suggesting that BDNF may regulate excitatory synapses and PSD95 dendritic clustering at least in part by changing the acetylation level of cortactin. Our findings unravel an unsuspected role for cortactin acetylation in the regulation of PSD95 dendritic clustering, which may work in concert with cortactin's role in spine development.

HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons

“…Under control conditions, in situ acetyl-cortactin immunoreactivity was primarily detected in proximal neurites (Fig. 3C), with some cortical and striatal neurons showing nuclear immunoreactivity, as previously reported for hippocampal neurons [35]. Treatment with TBA increased neuronal acetyl-cortactin immunoreactivity in situ (Fig.…”

“…3D). The function of acetyl-cortactin in neurons is mostly unknown [35]; however, (Fig. 4B,C), as previously described [31,38].…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Recently, Cortactin acetylation was also shown to affect dendritic spine morphogenesis, promoting the dendritic clustering of PSD95 and Shank1, two post-synaptic proteins, in excitatory hippocampal synapses. Cortactin acetylation can be promoted through BDNF and glutamate stimulation [191].…”

The Many Faces of Elongator in Neurodevelopment and Disease

“…The local regulation of Elongator may enable single active zones to control neurotransmitter release and may hold the key to synaptic transmission regulation. The importance of protein acetylation in regulation of synapse composition and functionality in neurons has been demonstrated by recent study (Catarino et al, 2013). The possible role of Elongator in vesicular trafficking, exocytosis and synaptic transmission using above mentioned mechanisms remains to be tested in humans, yet evolutionary conservation of Elongator implies that it may play a similar role.…”